The release of glutamate at synapses at many sites in mammalian forebrain stimulates two classes of postsynaptic ionotropic receptors. These classes are usually referred to as AMPA/quisqualate and N-methyl-D-aspartic acid (NMDA) receptors. AMPA/quisqualate receptors mediate a voltage independent fast excitatory post-synaptic current (the fast epsc) whereas NMDA receptors generate a voltage-dependent, slow excitatory current. Studies carried out in slices of hippocampus or cortex indicate that the AMPA receptor-mediated fast epsc is by far the dominant component at most glutamatergic synapses under most circumstances.
AMPA receptors are not evenly distributed across the brain but instead are largely restricted to telencephalon and cerebellum. These receptors are found in high concentrations in the superficial layers of neocortex, in each of the major synaptic zones of hippocampus, and in the striatal complex, as reported by Monaghan et al., in Brain Research 324:160-164 (1984). Studies in animals and humans indicate that these structures organize complex perceptual-motor processes and provide the substrates for higher-order behaviors. Thus, AMPA receptors mediate transmission in those brain networks responsible for a host of cognitive activities.
For the reasons set forth above, drugs that enhance the functioning of AMPA receptors could have significant benefits for cognitive performance. Such drugs should also facilitate memory encoding. Experimental studies, such as those reported by Arai and Lynch, Brain Research, 598:173-184 (1992), indicate that increasing the size of AMPA receptor-mediated synaptic response(s) enhances the induction of long-term potentiation (LTP). LTP is a stable increase in the strength of synaptic contacts that follows repetitive physiological activity of a type known to occur in the brain during learning. Compounds that enhance the functioning of the AMPA form of glutamate receptors facilitate the induction of LTP and the acquisition of learned tasks as measured by a number of paradigms. Granger et al., Synapse 15:326-329 (1993); Staubli et al., PNAS 91:777-781 (1994); Arai et al., Brain Res. 638:343-346 (1994); Staubli et al., PNAS 91:11158-1162 (1994); Shors et al., Neurosci. Let. 186:153-156 (1995); Larson et al., J. Neurosci. 15:8023-8030 (1995); Granger et al., Synapse 22:332-337 (1996); Arai, et al., JPET 278:627-638 (1996); Lynch et al., Internat. Clin. Psychopharm. 11:13-19 (1996); Lynch et al., Exp. Neurology 145:89-92 (1997); Ingvar et al., Exp. Neurology 146:553-559 (1997); Hampson et al., J. Neurosci., 18:2740-2747 (1998); Hampson, et al., J. Neurosci., 18:2748-2763 (1998) and International Patent Application Publication No. WO 94/02475 (PCT/US93/06916) (Lynch and Rogers, Regents of the University of California).
There is a considerable body of evidence showing that LTP is the substrate of memory. For example, compounds that block LTP interfere with memory formation in animals, and certain drugs that disrupt learning in humans antagonize the stabilization of LTP, as reported by del Cerro and Lynch, Neuroscience 49:1-6 (1992). A possible prototype for a compound that selectively facilitates the AMPA receptor was disclosed by Ito et al., J. Physiol. 424:533-543 (1990). These authors found that the nootropic drug aniracetam (N-anisoyl-2-pyrrolidinone) increases currents mediated by brain AMPA receptors expressed in Xenopus oocytes without affecting responses by .gamma.-aminobutyric acid (GABA), kainic acid (KA), or NMDA receptors. Infusion of aniracetam into slices of hippocampus was also shown to substantially increase the size of fast synaptic potentials without altering resting membrane properties. It has since been confirmed that aniracetam enhances synaptic responses at several sites in hippocampus, and that it has no effect on NMDA-receptor mediated potentials. See, for example, Staubli et al., in Psychobiology 18:377-381 (1990) and Xiao et al., Hippocampus 1:373-380 (1991). Aniracetam has also been found to have an extremely rapid onset and washout, and can be applied repeatedly with no apparent lasting effects; these are valuable traits for behaviorally-relevant drugs. Unfortunately, the peripheral administration of aniracetam is not likely to influence brain receptors. The drug works only at high concentrations (.about.1.0 mM) and Guenzi and Zanetti, J. Chromatogr. 530:397-406 (1990) report that about 80% of the drug is hydrolyzed to anisoyl-GABA following peripheral administration in humans. The metabolite, anisoyl-GABA, has been found to have only weak aniracetam-like effects.
A class of compounds that do not display the low potency and inherent hydrolytic instability characteristic of aniracetam has recently been disclosed. These compounds, termed "Ampakines", are disclosed in International Patent Application Publication No. WO 94/02475 (PCT/US93/06916) (Lynch and Rogers, Regents of the University of California). The Ampakines generally are substituted benzamides, are chemically more stable than aniracetam, and show improved bioavailability as judged by experiments performed by Positron Emission Tomography (PET) [see, for example, Staubli et al., in PNAS 91:11158-11162 (1994)]. Additional Ampakines in the form of benzoyl piperidines and pyrrolidines have also been discovered and are the subject of pending U.S. Pat. No. 5,650,450. A new class of Ampakines, benzoxazines, have been discovered recently to have unexpectedly high activity in in vitro and in vivo models for assessing the probability of producing cognition enhancement [Rogers and Lynch "Benzoxazines for Enhancing Synaptic Response", U.S. Pat. No. 5,736,543, issued Apr. 7, 1998. Further structure-activity development has uncovered a new series of compounds, acyl benzoxazines, that produce potent responses in in vitro assays of AMPA receptor activation and show significantly improved biostability compared to isomeric benzoxazines. These compounds are disclosed herein.